Molecular Pharmacology, Vol 11, 223-231, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Characteristics of the Amino Acid Receptor Site Mediating Formation of Cyclic Adenosine 3',5'-Monophosphate in Mammalian Brains

¹ Department of Pharmacology and Biochemistry, Nippon Roche Research Center, Kajiwara, Kamakura, Japan

Aliphatic -acidic -amino acids, which are known to cause neural cell excitation when applied iontophoretically to the central nervous system, were effective in increasing the concentrations of cyclic 3',5'-AMP in cerebral cortical slices of the guinea pig and rat. L-Cysteinesulfinic acid was the most powerful. Replacement of the sulfinyl group with a carboxyl group (aspartic acid) or a sulfonyl group (cysteic acid) reduced the activity to less than half that caused by the sulfinate. Elongation of the aliphatic carbon chain from aspartate (C₂) to glutamate (C₃) did not alter the activity, but further elongation to -aminoadipate (C₄) and -aminopimelate (C₅) decreased the activity in a manner depending on the chain length. L-Cysteinesulfinic acid was more powerful than its higher homologue. The L isomers of the enantiomorphs of active amino acids were more potent than the corresponding D isomers. However, there appeared to be no significant difference in the efficacy of the two stereoisomers at their optimal concentrations. The structure-activity relationships were similar with respect to both the amino acid-elicited accumulations of cyclic AMP in brain tissue and the iontophoretic effects on firing rates of spinal and cortical neurons.

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ACKNOWLEDGMENTS We wish to express our appreciation to Dr. J. W. Daly, Dr. T. Yamada, and Dr. L. M. Jampolsky for their critical reviews and thoughtful advice during the preparation of this paper.